Presentation portion of this Final Paper (in mp4 format because too long to upload to youtube)
An investigation into the synthesis and pharmaceutical applications of trans-dibenzalacetone and a few of its common derivatives
Introduction
This investigation focuses on the synthesis of trans-dibenzalacetone (compound 1) and a few of the health applications of some of the dibenzalacetone derivatives. The synthesis of dibenzalacetone is described in detail and the health applications of dibenzalacetone and its derivatives related to cancer treatment, malaria treatment, use as an antioxidant, use as a skin whitening agent, and use as an anti-bacterial agent are examined. For this investigation, a dibenzalacetone derivative is considered to be a compound that is synthesized using acetone and an aromatic aldehyde. The derivatives examined are symmetrical with different functional groups on the aromatic ring.
Compound 1: (1E,4E)-1,5-Diphenyl-1,4-pentadien-3-one CSID: 555548 Figure 1: The systematic name, ChemSpider ID, and structure for dibenzalacetone
Synthesis
The synthesis of trans-dibenzalacetone is commonly carried out in organic chemistry teaching laboratories. The reaction of benzaldehyde with acetone to form trans-dibenzalacetone clearly demonstrates an aldol condensation [1]. Benzaldehyde does not possess any alpha-hydrogens so it cannot undergo self-condensation, but it can undergo cross-condensation with another carbanion. Acetone has two sites of alpha-hydrogens and therefore can be reacted with two benzaldehyde molecules by undergoing two cross-condensations. Since benzaldehyde and acetone react in a 2:1 ratio to form trans-dibenzalacetone, the ratio of the reactants is important when planning the synthesis. A reaction mixture that has an excess of acetone will form benzalacetone in the form of an oil. An excess of benzaldehyde is needed to form trans-dibenzalacetone. To synthesize trans-dibenzalacetone, a 1.0M solution of benzaldehyde in ethanol is created and 40 mL of this solution is mixed with an equal amount of a 0.5M aqueous sodium hydroxide solution in a 250 mL beaker. As this solution is stirred, 0.5 mL of acetone is added to the solution. This reaction mixture is stirred for approximately 20 minutes at room temperature. The yellow dibenzalacetone crystals that form in the mixture are removed by vacuum filtration. The crystals can be recrystallized using aqueous ethanol [2]. Additionally, ethyl acetate can be used to recrystallize the product. The reaction is carried out in a basic environment due to the sodium hydroxide. Lower concentrations of sodium hydroxide can lead to undesired side products involving benzalacetone that does not react with a second molecule of benzaldehyde. Higher concentrations of sodium hydroxide lead to an increased amount of sodium carbonate impurity that can be difficult to remove from the product. However, since the product is highly insoluble in water, the product can be washed throughly with water in an effort to remove the sodium carbonate and other impurities [3]. The practicality of this synthesis is that any derivative of benzaldehyde could be used as long as the molecule does not have an alpha-hydrogen. By using a different aldehyde, the final product is changed. This method of using different aldehydes for this aldol condensation to form different products allows many different compounds to be synthesized using this procedure with a minimal number of modifications.
Figure 2: Synthesis scheme of dibenzalacetone [3].
Cancer Treatment
Dibenzalacetone and many of its derivatives have been investigated as potential treatments for cancer. Dibenzalacetone has been shown to cause cell death in colon cancer cells in a p53 independent manner. This is important because most cancer drugs target p53 activity and therefore there is a lack of drugs that can be used on cancer types that are p53 independent. There was a correlation between the cell death and the inhibition of isopeptidase activity. Consequently, it is believed that by inhibiting isopeptidase activity, dibenzalacetone was able to inhibit the proteasome pathway and cause cell death [4]. Many tumors grow larger by causing new blood vessel growth, known as angiogenesis. Dibenzalacetone has been identified as a potential angiogenesis inhibitor by inhibiting in vitro endothelial cell proliferation by 96.6% at a dosage of 3 µg/mL [5]. Dibenzalacetone derivatives have been examined to determine their inhibitory effect on the growth of human prostate cancer PC-3 cells, pancreas cancer Panc-1 cells, and colon cancer HT-29 cells. The derivative that had the lowest IC50 dosage for the prostate cancer cells was compound 2. This derivative also has demonstrated a high cytotoxicity against the human colon cancer cell line DLD-1 [6]. The derivative that had the lowest IC50 dosage for the pancreas cancer cells was compound 3 and the derivative that had the lowest IC50 dosage for the colon cancer cells was compound 4 [7]. Additionally, the derivative compound 5 has also demonstrated cytotoxicity toward the PC-3 prostate cell line with an IC50 of 2.4µM [8]. The transcription factor NFkappaB (NFκB) can promote survival in cells and discourage apoptosis from occurring. Consequently, many cancer cells up-regulate this transcription factor and so a compound that inhibits this transcription factor could potentially be used to decrease cancer cell growth and survival. The derivative compound 6 was demonstrated to inhibit the activation of the transcription factor NFκB [9]. Additionally, the derivative compound 4 has been shown to have an inhibitory effect on NFκB activation [10]. The nitrogen containing derivative compound 7 showed a modest inhibition of NFκB gene expression, but was not as effective as Curcumin [11]. A few of the derivatives have demonstrated the ability to inhibit 17β-hydroxysteroid dehydrogenase 3 which is involved in testosterone biosynthesis. This could be of use for treating androgen dependent diseases such as prostate cancer [12]. The derivatives have also demonstrated an ability to inhibit the growth of MDA-MB-231 breast cancer cells and it was shown that the presence of an ortho-hydroxy group is important for activity, since the derivative compound 8 had the lowest Gl50 of the dibenzalacetone derivatives [13]. The derivative compound 9 has demonstrated an apoptotic antitumor effect on human lung cancer cells. This antitumor effect was obtained through a endoplasmic reticulum stress mediated mechanism. Additionally, this derivative has low toxicity in mice, causing it to have great promise as a potential treatment for lung cancer [14].
Dibenzalacetone and a few of its derivatives have been tested for their activity against malaria. Compounds that have a rather simple synthesis and can be produced using cheaper materials are extremely valuable for treating a disease such as malaria. Dibenzalacetone was determined to have an IC50 of 32µM for the in vitro growth of the K1 strain of Plasmodium falciparum. Plasmodium falciparum is one of the species that causes malaria in humans. Dibenzalacetone was determined to be inactive against inhibiting the Plasmodium falciparum, since the IC50 was greater than 10µM. In comparison, chloroquine, which is a compound used to treat malaria, had an IC50 of 0.25µM. However, some 1,2,4,5-tetraoxane compounds showed activity against malaria with IC50s under 10µM [15]. While dibenzalacetone is not active against Plasmodium falciparum, the derivative compound 2 has demonstrated significant activity against malaria. This derivative had an IC50 of 1.97µM against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum and an IC50 of 1.69µM against the chloroquine-resistant RKL9 strain. It was determined that for the symmetrical dibenzalacetone derivatives, the placement of electron donating groups at the meta and para positions and an electron withdrawing group at the ortho position favorably increases the activity of the compound against malaria [16].
Antioxidant
Compounds that can act as antioxidants are useful as potential chemopreventive agents and for protecting red blood cells from oxidative haemolysis. A few of the dibenzalacetone derivatives have been investigated for their ability to act as antioxidants. The derivative compound 10 was the most active of the dibenzalacetone derivatives tested with an IC50 of 9.63µM for 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging. DPPH is a relatively stable nitrogen radical and will be reduced when reacting with a hydrogen donor. This radical is commonly used for measuring the antioxidant properties of a compound [17]. Additionally, the derivative compound 5 has demonstrated antioxidant activity by inhibiting the auto-oxidization of linoleic acid [18].
Anti-Melanogenesis
Melanogensis is the process of the skin producing protective agents against the harmful effects of ultraviolet radiation. This is accomplished by the melanins in skin cells absorbing free radicals and this can cause discoloration. The derivative compound 11 demonstrated anti-tyrosinase activity, but had little effect on tyrosinase expression in B16 melanoma cells. This inhibition of tyrosinase is important for preventing the cell pigmentation that leads to discoloration. Further research needs to be conducted before a dibenzalacetone derivative could be used as a skin whitening agent [19].
Anti-Bacterial
With the increasing number of antibiotic resistent strains of bacteria, more compounds that can act as a treatment for bacterial diseases are being investigated. Dibenzalacetone derivatives have demonstrated activity against both Gram-positive and Gram-negative strains of bacteria. Most importantly, the derivatives were shown to be active against the Gram negative Enterobacter cloacae bacteria. This strain of bacteria is resistent to the clinical drug ampicillin and therefore it is vital to find additional compounds that can be used to treat disease caused by this strain of bacteria [20].
Conclusion
Trans-dibenzalacetone can be synthesized rather simply using benzaldehyde and acetone in a 2:1 ratio. Dibenzalacetone and its derivatives have shown potential as treatments for various health issues. There are derivatives that show promise as cancer and malaria treatments. Some derivatives have been examined as antioxidants and as potential skin whitening agents. There are derivatives being considered as an alternative option for treating certain bacterial diseases. This dibenzalacetone family of compounds is rich with potential pharmaceutical applications for improving health and fighting many different diseases.
References
1. Hull, L. A. (2001). The Dibenzalacetone Reaction Revisited. Journal of Chemical Education, 78(2), 226. DOI
2. Hawbecker, B. L., Kurtz, D. W., Putnam, T. D., & Ahlers, P. A. (1978). The Aldol Condensation: A Simple Teaching Model for Organic Laboratory. Journal of Chemical Education, 55(8), 540–1. DOI
3. Conard, C. R., & Dolliver, M. A. (1943). DIBENZALACETONE. Organic Syntheses, 2, 167. DOI
4. Mullally, J. E., & Fitzpatrick, F. A. (2002). Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases that Induce p53-independent Cell Death. Molecular Pharmacology, 62(2), 351–8. DOI
5. Robinson, T. P., Ehlers, T., Hubbard IV, R. B., Bai, X., Arbiser, J. L., Goldsmith, D. J., & Bowen, J. P. (2003). Design, Synthesis, and Biological Evaluation of Angiogenesis Inhibitors: Aromatic Enone and Dienone Analogues of Curcumin. Bioorganic & Medicinal Chemistry Letters, 13(1), 115–7. DOI
6. Yamakoshi, H., Ohori, H., Kudo, C., Sato, A., Kanoh, N., Ishioka, C., Shibata, H., et al. (2010). Structure-activity Relationship of C5-curcuminoids and Synthesis of their Molecular Probes Thereof. Bioorganic & Medicinal Chemistry, 18(3), 1083–92. DOI
7. Wei, X., Du, Z.-Y., Zheng, X., Cui, X.-X., Conney, A. H., & Zhang, K. (2012). Synthesis and Evaluation of Curcumin-related Compounds for Anticancer Activity. European Journal of Medicinal Chemistry, 53, 235–45. DOI
8. Lin, L., Shi, Q., Nyarko, A. K., Bastow, K. F., Wu, C.-C., Su, C.-Y., Shih, C. C.-Y., et al. (2006). Antitumor Agents. 250. Design and Synthesis of New Curcumin Analogues as Potential Anti-Prostate Cancer Agents. Journal of Medicinal Chemistry, 49(13), 3963–72. DOI
9. Weber, W. M., Hunsaker, L. A., Roybal, C. N., Bobrovnikova-Marjon, E. V., Abcouwer, S. F., Royer, R. E., Deck, L. M., et al. (2006). Activation of NFkappaB is Inhibited by Curcumin and Related Enones. Bioorganic & Medicinal Chemistry, 14(7), 2450–61. DOI
10. Qiu, X., Du, Y., Lou, B., Zuo, Y., Shao, W., Huo, Y., Huang, J., et al. (2010). Synthesis and Identification of New 4-Arylidene Curcumin Analogues as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway. Journal of Medicinal Chemistry, 53(23), 8260–73. DOI
11. Aggarwal, S., Ichikawa, H., Takada, Y., Sandur, S. K., Shishodia, S., & Aggarwal, B. B. (2006). Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IkBa Kinase and Akt Activation. Molecular Pharmacology, 69(1), 195–206. DOI
13. Adams, B. K., Ferstl, E. M., Davis, M. C., Herold, M., Kurtkaya, S., Camalier, R. F., Hollingshead, M. G., et al. (2004). Synthesis and Biological Evaluation of Novel Curcumin Analogs as Anti-cancer and Anti-angiogenesis Agents. Bioorganic & Medicinal Chemistry, 12(14), 3871–83. DOI
14. Wang, Y., Xiao, J., Zhou, H., Yang, S., Wu, X., Jiang, C., Zhao, Y., et al. (2011). A Novel Monocarbonyl Analogue of Curcumin, (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, Induced Cancer Cell H460 Apoptosis via Activation of Endoplasmic Reticulum Stress Signaling Pathway. Journal of Medicinal Chemistry, 54, 3768–78. DOI
15. Franco, L. L., Vieira de Almeida, M., Rocha e Silva, L. F., Vieira, P. P. R., Pohlit, A. M., & Valle, M. S. (2012). Synthesis and Antimalarial Activity of Dihydroperoxides and Tetraoxanes Conjugated with Bis(benzyl)acetone Derivatives. Chemical Biology & Drug Design, 79, 790–7. DOI
16. Aher, R. B., Wanare, G., Kawathekar, N., Kumar, R. R., Kaushik, N. K., Sahal, D., & Chauhan, V. S. (2011). Dibenzylideneacetone Analogues as Novel Plasmodium falciparum Inhibitors. Bioorganic & Medicinal Chemistry Letters, 21(10), 3034–6. DOI
17. Shang, Y.-J., Jin, X.-L., Shang, X.-L., Tang, J.-J., Liu, G.-Y., Dai, F., Qian, Y.-P., et al. (2010). Antioxidant Capacity of Curcumin-Directed Analogues: Structure–Activity Relationship and Influence of Microenvironment. Food Chemistry, 119(4), 1435–42. DOI
18. Masuda, T., Jitoe, A., Isobe, J., Nakatani, N., & Yonemori, S. (1993). Anti-oxidative and Anti-inflammatory Curcumin-related Phenolics from Rhizomes of Curcuma domestica. Phytochemistry, 32(6), 1557–60. DOI
19. Hosoya, T., Nakata, A., Yamasaki, F., Abas, F., Shaari, K., Lajis, N. H., & Morita, H. (2012). Curcumin-like Diarylpentanoid Analogues as Melanogenesis Inhibitors. Journal of Natural Medicines, 66, 166–76. DOI
20. Liang, G., Yang, S., Jiang, L., Zhao, Y., Shao, L., Xiao, J., Ye, F., et al. (2008). Synthesis and Anti-bacterial Properties of Mono-carbonyl Analogues of Curcumin. Chemical & Pharmaceutical Bulletin, 56(2), 162–7. DOI
Final Paper
CHEM 367Matthew McBride
Presentation portion of this Final Paper (in mp4 format because too long to upload to youtube)
An investigation into the synthesis and pharmaceutical applications of trans-dibenzalacetone and a few of its common derivatives
Introduction
This investigation focuses on the synthesis of trans-dibenzalacetone (compound 1) and a few of the health applications of some of the dibenzalacetone derivatives. The synthesis of dibenzalacetone is described in detail and the health applications of dibenzalacetone and its derivatives related to cancer treatment, malaria treatment, use as an antioxidant, use as a skin whitening agent, and use as an anti-bacterial agent are examined. For this investigation, a dibenzalacetone derivative is considered to be a compound that is synthesized using acetone and an aromatic aldehyde. The derivatives examined are symmetrical with different functional groups on the aromatic ring.Compound 1: (1E,4E)-1,5-Diphenyl-1,4-pentadien-3-one CSID: 555548
Figure 1: The systematic name, ChemSpider ID, and structure for dibenzalacetone
Synthesis
The synthesis of trans-dibenzalacetone is commonly carried out in organic chemistry teaching laboratories. The reaction of benzaldehyde with acetone to form trans-dibenzalacetone clearly demonstrates an aldol condensation [1]. Benzaldehyde does not possess any alpha-hydrogens so it cannot undergo self-condensation, but it can undergo cross-condensation with another carbanion. Acetone has two sites of alpha-hydrogens and therefore can be reacted with two benzaldehyde molecules by undergoing two cross-condensations. Since benzaldehyde and acetone react in a 2:1 ratio to form trans-dibenzalacetone, the ratio of the reactants is important when planning the synthesis. A reaction mixture that has an excess of acetone will form benzalacetone in the form of an oil. An excess of benzaldehyde is needed to form trans-dibenzalacetone. To synthesize trans-dibenzalacetone, a 1.0M solution of benzaldehyde in ethanol is created and 40 mL of this solution is mixed with an equal amount of a 0.5M aqueous sodium hydroxide solution in a 250 mL beaker. As this solution is stirred, 0.5 mL of acetone is added to the solution. This reaction mixture is stirred for approximately 20 minutes at room temperature. The yellow dibenzalacetone crystals that form in the mixture are removed by vacuum filtration. The crystals can be recrystallized using aqueous ethanol [2]. Additionally, ethyl acetate can be used to recrystallize the product. The reaction is carried out in a basic environment due to the sodium hydroxide. Lower concentrations of sodium hydroxide can lead to undesired side products involving benzalacetone that does not react with a second molecule of benzaldehyde. Higher concentrations of sodium hydroxide lead to an increased amount of sodium carbonate impurity that can be difficult to remove from the product. However, since the product is highly insoluble in water, the product can be washed throughly with water in an effort to remove the sodium carbonate and other impurities [3]. The practicality of this synthesis is that any derivative of benzaldehyde could be used as long as the molecule does not have an alpha-hydrogen. By using a different aldehyde, the final product is changed. This method of using different aldehydes for this aldol condensation to form different products allows many different compounds to be synthesized using this procedure with a minimal number of modifications.Figure 2: Synthesis scheme of dibenzalacetone [3].
Cancer Treatment
Dibenzalacetone and many of its derivatives have been investigated as potential treatments for cancer. Dibenzalacetone has been shown to cause cell death in colon cancer cells in a p53 independent manner. This is important because most cancer drugs target p53 activity and therefore there is a lack of drugs that can be used on cancer types that are p53 independent. There was a correlation between the cell death and the inhibition of isopeptidase activity. Consequently, it is believed that by inhibiting isopeptidase activity, dibenzalacetone was able to inhibit the proteasome pathway and cause cell death [4]. Many tumors grow larger by causing new blood vessel growth, known as angiogenesis. Dibenzalacetone has been identified as a potential angiogenesis inhibitor by inhibiting in vitro endothelial cell proliferation by 96.6% at a dosage of 3 µg/mL [5]. Dibenzalacetone derivatives have been examined to determine their inhibitory effect on the growth of human prostate cancer PC-3 cells, pancreas cancer Panc-1 cells, and colon cancer HT-29 cells. The derivative that had the lowest IC50 dosage for the prostate cancer cells was compound 2. This derivative also has demonstrated a high cytotoxicity against the human colon cancer cell line DLD-1 [6]. The derivative that had the lowest IC50 dosage for the pancreas cancer cells was compound 3 and the derivative that had the lowest IC50 dosage for the colon cancer cells was compound 4 [7]. Additionally, the derivative compound 5 has also demonstrated cytotoxicity toward the PC-3 prostate cell line with an IC50 of 2.4µM [8]. The transcription factor NFkappaB (NFκB) can promote survival in cells and discourage apoptosis from occurring. Consequently, many cancer cells up-regulate this transcription factor and so a compound that inhibits this transcription factor could potentially be used to decrease cancer cell growth and survival. The derivative compound 6 was demonstrated to inhibit the activation of the transcription factor NFκB [9]. Additionally, the derivative compound 4 has been shown to have an inhibitory effect on NFκB activation [10]. The nitrogen containing derivative compound 7 showed a modest inhibition of NFκB gene expression, but was not as effective as Curcumin [11]. A few of the derivatives have demonstrated the ability to inhibit 17β-hydroxysteroid dehydrogenase 3 which is involved in testosterone biosynthesis. This could be of use for treating androgen dependent diseases such as prostate cancer [12]. The derivatives have also demonstrated an ability to inhibit the growth of MDA-MB-231 breast cancer cells and it was shown that the presence of an ortho-hydroxy group is important for activity, since the derivative compound 8 had the lowest Gl50 of the dibenzalacetone derivatives [13]. The derivative compound 9 has demonstrated an apoptotic antitumor effect on human lung cancer cells. This antitumor effect was obtained through a endoplasmic reticulum stress mediated mechanism. Additionally, this derivative has low toxicity in mice, causing it to have great promise as a potential treatment for lung cancer [14].Compound 2: (1E,4E)-1,5-Bis(3,4-dimethoxyphenyl)-1,4-pentadien-3-one CSID: 1155046
Compound 3: (1E,4E)-1,5-Bis(4-hydroxy-3,5-dimethoxyphenyl)-1,4-pentadien-3-one CSID: 8866878
Compound 4: (1E,4E)-1,5-Bis(3,4,5-trimethoxyphenyl)-1,4-pentadien-3-one CSID: 1267015
Compound 5: (1E,4E)-1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one CSID: 4976777
Compound 6: (1E,4E)-1,5-Bis(2,5-dimethoxyphenyl)-1,4-pentadien-3-one CSID: 9007269
Compound 7: (1E,4E)-1,5-Bis[4-(dimethylamino)phenyl]-1,4-pentadien-3-one CSID: 686939
Compound 8: (1E,4E)-1,5-Bis(2-hydroxyphenyl)-1,4-pentadien-3-one CSID: 4582719
Compound 9: (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)-1,4-pentadien-3-one CSID: 958117
Compound 10: (1E,4E)-1,5-Bis(3,4-dihydroxyphenyl)-1,4-pentadien-3-one CSID: 4976778
Compound 11: (1E,4E)-1,5-Bis(4-hydroxyphenyl)-1,4-pentadien-3-one CSID: 4941874
Figure 3: The systematic name, ChemSpider ID, and structure for dibenzalacetone derivatives 2-11
Malaria Treatment
Dibenzalacetone and a few of its derivatives have been tested for their activity against malaria. Compounds that have a rather simple synthesis and can be produced using cheaper materials are extremely valuable for treating a disease such as malaria. Dibenzalacetone was determined to have an IC50 of 32µM for the in vitro growth of the K1 strain of Plasmodium falciparum. Plasmodium falciparum is one of the species that causes malaria in humans. Dibenzalacetone was determined to be inactive against inhibiting the Plasmodium falciparum, since the IC50 was greater than 10µM. In comparison, chloroquine, which is a compound used to treat malaria, had an IC50 of 0.25µM. However, some 1,2,4,5-tetraoxane compounds showed activity against malaria with IC50s under 10µM [15]. While dibenzalacetone is not active against Plasmodium falciparum, the derivative compound 2 has demonstrated significant activity against malaria. This derivative had an IC50 of 1.97µM against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum and an IC50 of 1.69µM against the chloroquine-resistant RKL9 strain. It was determined that for the symmetrical dibenzalacetone derivatives, the placement of electron donating groups at the meta and para positions and an electron withdrawing group at the ortho position favorably increases the activity of the compound against malaria [16].Antioxidant
Compounds that can act as antioxidants are useful as potential chemopreventive agents and for protecting red blood cells from oxidative haemolysis. A few of the dibenzalacetone derivatives have been investigated for their ability to act as antioxidants. The derivative compound 10 was the most active of the dibenzalacetone derivatives tested with an IC50 of 9.63µM for 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging. DPPH is a relatively stable nitrogen radical and will be reduced when reacting with a hydrogen donor. This radical is commonly used for measuring the antioxidant properties of a compound [17]. Additionally, the derivative compound 5 has demonstrated antioxidant activity by inhibiting the auto-oxidization of linoleic acid [18].Anti-Melanogenesis
Melanogensis is the process of the skin producing protective agents against the harmful effects of ultraviolet radiation. This is accomplished by the melanins in skin cells absorbing free radicals and this can cause discoloration. The derivative compound 11 demonstrated anti-tyrosinase activity, but had little effect on tyrosinase expression in B16 melanoma cells. This inhibition of tyrosinase is important for preventing the cell pigmentation that leads to discoloration. Further research needs to be conducted before a dibenzalacetone derivative could be used as a skin whitening agent [19].Anti-Bacterial
With the increasing number of antibiotic resistent strains of bacteria, more compounds that can act as a treatment for bacterial diseases are being investigated. Dibenzalacetone derivatives have demonstrated activity against both Gram-positive and Gram-negative strains of bacteria. Most importantly, the derivatives were shown to be active against the Gram negative Enterobacter cloacae bacteria. This strain of bacteria is resistent to the clinical drug ampicillin and therefore it is vital to find additional compounds that can be used to treat disease caused by this strain of bacteria [20].Conclusion
Trans-dibenzalacetone can be synthesized rather simply using benzaldehyde and acetone in a 2:1 ratio. Dibenzalacetone and its derivatives have shown potential as treatments for various health issues. There are derivatives that show promise as cancer and malaria treatments. Some derivatives have been examined as antioxidants and as potential skin whitening agents. There are derivatives being considered as an alternative option for treating certain bacterial diseases. This dibenzalacetone family of compounds is rich with potential pharmaceutical applications for improving health and fighting many different diseases.References
1. Hull, L. A. (2001). The Dibenzalacetone Reaction Revisited. Journal of Chemical Education, 78(2), 226. DOI2. Hawbecker, B. L., Kurtz, D. W., Putnam, T. D., & Ahlers, P. A. (1978). The Aldol Condensation: A Simple Teaching Model for Organic Laboratory. Journal of Chemical Education, 55(8), 540–1. DOI
3. Conard, C. R., & Dolliver, M. A. (1943). DIBENZALACETONE. Organic Syntheses, 2, 167. DOI
4. Mullally, J. E., & Fitzpatrick, F. A. (2002). Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases that Induce p53-independent Cell Death. Molecular Pharmacology, 62(2), 351–8. DOI
5. Robinson, T. P., Ehlers, T., Hubbard IV, R. B., Bai, X., Arbiser, J. L., Goldsmith, D. J., & Bowen, J. P. (2003). Design, Synthesis, and Biological Evaluation of Angiogenesis Inhibitors: Aromatic Enone and Dienone Analogues of Curcumin. Bioorganic & Medicinal Chemistry Letters, 13(1), 115–7. DOI
6. Yamakoshi, H., Ohori, H., Kudo, C., Sato, A., Kanoh, N., Ishioka, C., Shibata, H., et al. (2010). Structure-activity Relationship of C5-curcuminoids and Synthesis of their Molecular Probes Thereof. Bioorganic & Medicinal Chemistry, 18(3), 1083–92. DOI
7. Wei, X., Du, Z.-Y., Zheng, X., Cui, X.-X., Conney, A. H., & Zhang, K. (2012). Synthesis and Evaluation of Curcumin-related Compounds for Anticancer Activity. European Journal of Medicinal Chemistry, 53, 235–45. DOI
8. Lin, L., Shi, Q., Nyarko, A. K., Bastow, K. F., Wu, C.-C., Su, C.-Y., Shih, C. C.-Y., et al. (2006). Antitumor Agents. 250. Design and Synthesis of New Curcumin Analogues as Potential Anti-Prostate Cancer Agents. Journal of Medicinal Chemistry, 49(13), 3963–72. DOI
9. Weber, W. M., Hunsaker, L. A., Roybal, C. N., Bobrovnikova-Marjon, E. V., Abcouwer, S. F., Royer, R. E., Deck, L. M., et al. (2006). Activation of NFkappaB is Inhibited by Curcumin and Related Enones. Bioorganic & Medicinal Chemistry, 14(7), 2450–61. DOI
10. Qiu, X., Du, Y., Lou, B., Zuo, Y., Shao, W., Huo, Y., Huang, J., et al. (2010). Synthesis and Identification of New 4-Arylidene Curcumin Analogues as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway. Journal of Medicinal Chemistry, 53(23), 8260–73. DOI
11. Aggarwal, S., Ichikawa, H., Takada, Y., Sandur, S. K., Shishodia, S., & Aggarwal, B. B. (2006). Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IkBa Kinase and Akt Activation. Molecular Pharmacology, 69(1), 195–206. DOI
12. Hu, G.-X., Liang, G., Chu, Y., Li, X., Lian, Q.-Q., Lin, H., He, Y., et al. (2010). Curcumin Derivatives Inhibit Testicular 17beta-hydroxysteroid Dehydrogenase 3. Bioorganic & Medicinal Chemistry Letters, 20(8), 2549–51. DOI
13. Adams, B. K., Ferstl, E. M., Davis, M. C., Herold, M., Kurtkaya, S., Camalier, R. F., Hollingshead, M. G., et al. (2004). Synthesis and Biological Evaluation of Novel Curcumin Analogs as Anti-cancer and Anti-angiogenesis Agents. Bioorganic & Medicinal Chemistry, 12(14), 3871–83. DOI
14. Wang, Y., Xiao, J., Zhou, H., Yang, S., Wu, X., Jiang, C., Zhao, Y., et al. (2011). A Novel Monocarbonyl Analogue of Curcumin, (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, Induced Cancer Cell H460 Apoptosis via Activation of Endoplasmic Reticulum Stress Signaling Pathway. Journal of Medicinal Chemistry, 54, 3768–78. DOI
15. Franco, L. L., Vieira de Almeida, M., Rocha e Silva, L. F., Vieira, P. P. R., Pohlit, A. M., & Valle, M. S. (2012). Synthesis and Antimalarial Activity of Dihydroperoxides and Tetraoxanes Conjugated with Bis(benzyl)acetone Derivatives. Chemical Biology & Drug Design, 79, 790–7. DOI
16. Aher, R. B., Wanare, G., Kawathekar, N., Kumar, R. R., Kaushik, N. K., Sahal, D., & Chauhan, V. S. (2011). Dibenzylideneacetone Analogues as Novel Plasmodium falciparum Inhibitors. Bioorganic & Medicinal Chemistry Letters, 21(10), 3034–6. DOI
17. Shang, Y.-J., Jin, X.-L., Shang, X.-L., Tang, J.-J., Liu, G.-Y., Dai, F., Qian, Y.-P., et al. (2010). Antioxidant Capacity of Curcumin-Directed Analogues: Structure–Activity Relationship and Influence of Microenvironment. Food Chemistry, 119(4), 1435–42. DOI
18. Masuda, T., Jitoe, A., Isobe, J., Nakatani, N., & Yonemori, S. (1993). Anti-oxidative and Anti-inflammatory Curcumin-related Phenolics from Rhizomes of Curcuma domestica. Phytochemistry, 32(6), 1557–60. DOI
19. Hosoya, T., Nakata, A., Yamasaki, F., Abas, F., Shaari, K., Lajis, N. H., & Morita, H. (2012). Curcumin-like Diarylpentanoid Analogues as Melanogenesis Inhibitors. Journal of Natural Medicines, 66, 166–76. DOI
20. Liang, G., Yang, S., Jiang, L., Zhao, Y., Shao, L., Xiao, J., Ye, F., et al. (2008). Synthesis and Anti-bacterial Properties of Mono-carbonyl Analogues of Curcumin. Chemical & Pharmaceutical Bulletin, 56(2), 162–7. DOI